This application proposes a five-year mentored research and training experience that will prepare Dr. Philip Boone to be a leader in the fields of medical neurogenetics, genomics, and disease modeling. The candidate has an MD and PhD in Molecular and Human Genetics from Baylor College of Medicine, where he studied genomic structural variation and Mendelian disease with Dr. James Lupski. He is now completing residency training in Pediatrics and Clinical Genetics at Boston Children?s Hospital (BCH) while pursuing postdoctoral training with Dr. Michael Talkowski at Massachusetts General Hospital (MGH) and the Broad Institute. Dr. Boone?s career goal is to become a physician-scientist and to advance care for patients with genetic disease. This project will greatly advance those goals and facilitate foundational discoveries for his independent research program as he seeks to delineate a new class of neurogenetic disease: the disorders of genome organization. This emerging class of genomic disorders involve mutations encoding components that regulate the 3D organization of chromosomes. This work will elucidate the molecular and phenotypic consequences of mutation of these genes. Specifically, Dr. Boone proposes to: 1) model these disorders using patient-derived and CRISPR-generated iPSC and neural lineage cell lines; 2) Characterize alterations to the 3D genome (via Hi-C) and transcriptome (via RNA-seq), as well as the human phenotype (via exams and history); and 3) Attempt to correct these defects in cellular models via CRISPRa/i of genes in this network. The work will improve the diagnosis and understanding of these disorders and lay the groundwork for targeted therapy. It will also generate fundamental knowledge about the spatial organization of the genome and the regulatory purpose it serves. The career development plan includes training in in vitro neurodevelopmental disease modeling, design and analysis of functional genomic experiments, and cohort building. The candidate will learn all the requisite skills needed for an independent research career, including supervising trainees and staff, responsible conduct of research, grant writing, scientific communication, and lab management. His primary mentor, Dr. Michael Talkowski, is Associate Professor of Neurology at MGH and Institute Member at the Broad Institute. Dr. Talkowski is an experienced mentor and recognized expert in statistical, computational, and functional genomics. His co-mentor, Dr. Gusella, is a renowned molecular geneticist with considerable experience in disease modeling and molecular mechanisms. The mentorship committee also includes diverse expertise in genome organization and neuronal function (Drs. Leonid Mirny and Kristen Brennand), clinical phenotyping (Dr. Angela Lin), and genetic counseling (Diane Lucente). Dr. Boone thus has access to the unique convergence of leading-edge genomics training environments at MGH, Harvard, MIT, and the Broad Institute, and remarkable physician- scientist training at MGH and BCH. Dr. Boone, his mentors, and their institutions are fully committed to this proposal and to his goal of becoming an independent physician-scientist and leader in clinical neurogenetics.